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Publication

Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics.

Molecular cell | 2019

Membrane targeting of the BECN1-containing class III PI 3-kinase (PI3KC3) complexes is pivotal to the regulation of autophagy. The interaction of PI3KC3 complex II and its ubiquitously expressed inhibitor, Rubicon, was mapped to the first β sheet of the BECN1 BARA domain and the UVRAG BARA2 domain by hydrogen-deuterium exchange and cryo-EM. These data suggest that the BARA β sheet 1 unfolds to directly engage the membrane. This mechanism was confirmed using protein engineering, giant unilamellar vesicle assays, and molecular simulations. Using this mechanism, a BECN1 β sheet-1 derived peptide activates both PI3KC3 complexes I and II, while HIV-1 Nef inhibits complex II. These data reveal how BECN1 switches on and off PI3KC3 binding to membranes. The observations explain how PI3KC3 inhibition by Rubicon, activation by autophagy-inducing BECN1 peptides, and inhibition by HIV-1 Nef are mediated by the switchable ability of the BECN1 BARA domain to partially unfold and insert into membranes.

Pubmed ID: 30581147 RIS Download

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Associated grants

Agency: NIGMS NIH HHS, United States
Id: P01 GM051487
Agency: NIGMS NIH HHS, United States
Id: T32 GM007232
Agency: NCI NIH HHS, United States
Id: K00 CA223029
Agency: NIGMS NIH HHS, United States
Id: R01 GM111730
Agency: NCI NIH HHS, United States
Id: F99 CA223029

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